A senescent-immune reserve niche model for incomplete lobular involution in the aging breast

Reviewer #1 (Public review):

Summary:

This Perspective proposes a conceptual model in which incomplete age-related lobular involution (ARLI) in the breast reflects an actively maintained senescent-immune "reserve niche," rather than simply passive failure of lobular regression after menopause. The authors aim to integrate breast cancer epidemiology, mammary gland biology, cellular senescence, immune surveillance, and comparative reserve-tissue systems to explain why persistent postmenopausal lobules are associated with increased breast cancer risk. The manuscript is ambitious, creative, and potentially useful in shifting attention from residual epithelial quantity alone toward the microenvironmental state of persistent lobules.

Strengths:

A major strength of the manuscript is its forward-looking synthesis. The authors bring together several areas that are often considered separately: ARLI as a tissue-level risk marker, inflammatory features of incompletely involuted breast tissue, senescence biology, macrophage-mediated remodeling, and the menopausal transition as a potential window of biological plasticity. The model is conceptually interesting and, if supported by future evidence, could stimulate new approaches to risk stratification and prevention focused on the perimenopausal period.

Weaknesses:

However, the current manuscript often presents the proposed model with more certainty than the available evidence supports. The evidence clearly supports associations among incomplete ARLI, inflammatory or immune features, and breast cancer risk, but it does not yet demonstrate that senescent cells maintain persistent lobules, that immune clearance failure causes incomplete involution, or that a self-sustaining senescent-immune "niche lock" exists in human breast tissue. Much of the mechanistic framework is extrapolated from other tissues, postpartum involution, or general senescence biology. These are reasonable sources for hypothesis generation, but the manuscript would be stronger if it more clearly distinguished established observations from inference and speculation.

The senescence component of the model requires stronger and more direct support. Several claims about senescent burden in the aging breast appear to rely on general senescence literature or mammary aging studies that do not directly demonstrate senescence in persistent human TDLUs. This distinction is important because the manuscript's central model depends on senescent cells being spatially and functionally linked to incomplete ARLI.

The epidemiologic evidence also requires a more balanced treatment. Although several studies support incomplete ARLI as a breast cancer risk-associated phenotype, other cohorts and quantitative approaches have reported attenuated or null associations. This mixed evidence is acknowledged, but it is treated largely as a caveat rather than incorporated into the central argument. For readers, this uncertainty is important for interpreting the strength and generalizability of the proposed model.

Reviewer #2 (Public review):

Summary:

This review constructs a novel theoretical framework to elucidate incomplete postmenopausal age-related lobular involution (ARLI) in the breast. Differing from the conventional view of persistent lobules as passive residual structures, the work innovatively defines them as an actively maintained senescence-immune reserve niche. It comprehensively integrates multidisciplinary evidence from breast epidemiology, stromal biology, cellular senescence and immune surveillance, as well as cross-tissue research findings, and identifies menopause as a core biological turning point regulating ARLI and relevant breast cancer risk, providing a new theoretical perspective for subsequent breast cancer risk assessment and preventive intervention research.

Strengths:

This study presents an original, logically rigorous, and well-organized research hypothesis. It innovatively breaks through the traditional cognitive perspective of ARLI and adopts a multidisciplinary and cross-tissue analytical approach to sort out relevant biological mechanisms systematically. The proposed theoretical framework is insightful, with good theoretical innovation and potential translational value for guiding breast cancer risk evaluation and targeted prevention strategies.

Weaknesses:

The manuscript currently serves primarily as a conceptual framework rather than a rigorously evidenced synthesis. Its central argument relies heavily on cross-sectional correlations and theoretical analogies to other organ systems, lacking operational definitions for the reserve state in human breast tissue.

Author response:

We thank the editors and reviewers for recognizing the originality and potential value of the proposed framework. The reviews rightly ask us to distinguish three things more sharply: what is established directly in human breast tissue, what is inferred from mammary and aging studies, and what remains hypothesis. We agree, and the revision will make that distinction explicit throughout.

We will define the proposed reserve state operationally and specify the findings that would distinguish active niche maintenance from passive persistence. Throughout, we will treat passive persistence as a legitimate competing hypothesis rather than a settled question. Heterogeneity and immune or inflammatory associations will be presented as consistent with active maintenance and causal directionality, not as establishing them. We will also integrate the mixed epidemiologic evidence more centrally into the argument, rather than treating it as a caveat.

We will reassess the evidence for senescence in the aging breast and describe it more precisely, correcting or narrowing statements that outrun the data. The figures will be revised so that observed inflammatory and immune-regulatory features are clearly separated from proposed senescence- and SASP-mediated mechanisms. We will also clarify the limits of our analogies: postpartum involution and cross-tissue reserve systems will be presented as sources of candidate mechanisms and testable predictions, not as direct evidence for the proposed mechanism in human ARLI. Finally, we will frame the translational implications as contingent. They depend on first demonstrating that senescent cells are enriched near persistent lobules, identifying the relevant cell types and immune states, and establishing causal relevance.

We appreciate the reviewers' constructive suggestions. We believe these revisions will preserve the conceptual contribution of the model while making its evidentiary status, the alternative explanations, and its falsifiable predictions substantially clearer.